Analysis of PAH Genetic Variation and Phenotypic Diversity in the PAHvdb

The Phenylalanine Hydroxylase Gene Locus-Specific Database and BIOPKU are public databases used to track genotypes in hyperphenylalaninemia. However, the rapidly expanding databases and evolving nomenclature standards require a comprehensive characterization of the current variant landscape. We performed a descriptive statistical analysis of PAH variant allocations, allele frequencies (AF%), and phenotypic annotations using PAHvdb database. Over the period 2022–2026, the PAHvdb expanded by 169.26%. Of the 3409 variants studied, 75.68% of the phenotypes were not assigned. Splicing-related mutations comprised approximately 4.37% of the database, with classic phenylketonuria phenotypes represented in both donor–acceptor and splice-region categories. Only 3.84% of the variants had enzymatic activity (EA%) data, which offer the most direct biochemical evidence for genotype–phenotype inference. The strong Spearman’s rank correlation coefficient (ρ) between EA% and APV (ρ = 0.745, p < 0.001) was consistent with the established relationship between residual PAH EA% and the severity of metabolic phenotype. The AF% distribution was markedly asymmetric and dominated by a small number of alleles that were most frequently reported in the database. These findings highlight the increasing clinical reliance on these databases. Our analysis highlights a heterogeneity of rare, uncharacterized variants of uncertain significance and underscores the need for unified, systematic reviews to standardize nomenclature and resolve phenotype–genotype discrepancies.